EP1210118B1 - Composition comprising a tramadol material and an anticonvulsant drug - Google Patents

Composition comprising a tramadol material and an anticonvulsant drug Download PDF

Info

Publication number
EP1210118B1
EP1210118B1 EP00957321A EP00957321A EP1210118B1 EP 1210118 B1 EP1210118 B1 EP 1210118B1 EP 00957321 A EP00957321 A EP 00957321A EP 00957321 A EP00957321 A EP 00957321A EP 1210118 B1 EP1210118 B1 EP 1210118B1
Authority
EP
European Patent Office
Prior art keywords
tramadol
pharmaceutical composition
ratio
pain
dimethylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP00957321A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1210118A2 (en
Inventor
Ellen E. Codd
Rebecca P. Martinez
Kathryn E. Rogers
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
Original Assignee
Ortho McNeil Pharmaceutical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ortho McNeil Pharmaceutical Inc filed Critical Ortho McNeil Pharmaceutical Inc
Priority to DK00957321T priority Critical patent/DK1210118T3/da
Publication of EP1210118A2 publication Critical patent/EP1210118A2/en
Application granted granted Critical
Publication of EP1210118B1 publication Critical patent/EP1210118B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to a pharmaceutical composition useful in the treatment of pain. More particularly, this invention is directed to a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug.
  • United States Patent No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring.
  • a series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim . Forsch ., (Drug Res.), 1978 , 28(I), 114.
  • Tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like (Driessen, et al., Arch. Pharmacol ., 1990 , 341, R104).
  • the Abstracts of the VI th World Congress on Pain, April 1-6 (1990) disclose that tramadol hydrochloride is an orally active pure agonist opioid analgesic.
  • tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim . Forsch ., (Drug Res.), 1978 , 28(I), 183), constipation (I.
  • tramadol When given at a dose of 50 mg by rapid i.v. injection, tramadol may produce certain side effects unique to tramadol including hot flushes and sweating. Despite these side effects, tramadol's 'atypical' combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently marketed as an analgesic.
  • Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects and, as a result, cannot always be given repeatedly or at high doses. The side effect problems are well documented in the literature. See, for example, T. Reisine and G. Pasternak in "Goodman and Gilman's, The Pharmacological Basis of Therapeutics", 9th edition; Hardman et al.; McGraw-Hill, New York, 1996; Chapter 23; pages 521-555 wherein it is disclosed that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
  • morphine and its congeners e.g., codeine, hydrocodone and oxycodone are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
  • opioids have been combined with other drugs, including non-opioid analgesic agents, which lower the amount of opioid needed to produce an equivalent degree of analgesia. It has been claimed that some of these combination products also have the advantage of requiring less of each ingredient while producing a synergistic analgesic effect.
  • Compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (inhibitory), additive or superadditive (A. Takemori, Annals New York Acad. Sci. , 1976 , 281, 262).
  • a combination of morphine and methadone, another opioid analgesic exhibits an additive effect (R.
  • United States Patent No. 4,571,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides superadditive effects when the components are within certain ratios. See also, U.S. Patent Nos. 4,587,252 and 4,569,937 which disclose other ibuprofen opioid combinations.
  • tramadol As an analgesic, tramadol has been combined with both opioid and non-opioid analgesic drugs. Such compositions have exhibited synergistic effects in treating pain while using less of each ingredient to produce an equivalent degree of analgesia.
  • U.S. Patent No. 5,516,803 discloses the composition of tramadol and a NSAID, particularly ibuprofen.
  • United States Patent No. 5,468,744 discloses tramadol plus any of oxycodone, codeine or hydrocodone and U.S. Patent No. 5,336,691 discloses tramadol in combination with acetaminophen.
  • anticonvulsant drugs are not known to be useful in the treatment of pain.
  • certain anticonvulsant drugs have been found useful in the treatment of neuropathic pain.
  • United States Patent No. 4,513,006 discloses a class of anticonvulsant drugs including the 2,3,4,5-bis-O-(1-methylethylidene)- ⁇ -D-fructopyranose sulfamates known as topiramate.
  • United States Patent No. 5,760,007 further discloses topiramate as useful for the treatment of neuropathic pain.
  • NMDA N-methyl-d-aspartate
  • NMDA N-methyl-d-aspartate
  • WO 98/07447 broadly discloses the combination of a neuropathic pain alleviating amount of an anticonvulsant drug, including gabapentin, lamotrigine, valproic acid, topiramate, famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione
  • Anticonvulsant drugs combined with NSAIDS or narcotic analgesics have also been described as useful in the treatment of pain.
  • WO 99/12537 discloses a composition of the anticonvulsant compounds gabapentin or pregabalin in combination with the NSAID naproxen or with narcotic analgesics. Combinations of anticonvulsants and other drugs with opioid analgesics have been suggested (Donnadieu, S., et al., Pain Relief, Presse Medicale, 1998 , 27/39, 2062-2069). These references, however, also do not teach the synergistic composition of the present invention.
  • a pharmaceutical composition comprising a combination of the centrally acting analgesic tramadol and an anticonvulsant drug demonstrating that such a composition has a synergistic effect while using less of each ingredient for treating conditions of pain and neurological or psychiatric disorders in mammals.
  • the present invention provides a combination product with a tramadol material having improved properties.
  • the present invention provides a combination product with a tramadol material and an anticonvulsant drug wherein the combination has a synergistic effect while using less of each ingredient.
  • the present invention provides a combination product with tramadol hydrochloride and an anticonvulsant drug selected from topiramate, gabapentin, lamotrigine or RWJ-333369; wherein the combination has a synergistic effect while using less of each ingredient.
  • a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug selected from topiramate, gabapentin, lamotrigine and RWJ-333 369, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective 50% effective dose (ED 50 ) values, which ratio is from about 1:1 to about 300:1 or from about 1:1 to about 1:300.
  • ED 50 effective dose
  • An embodiment of the pharmaceutical composition of the present invention comprises a combination of a tramadol material and said anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 100:1 or from about 1:1 to about 1:100.
  • composition of the present invention comprises a combination of a tramadol material and said anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 30:1 or from about 1:1 to about 1:30.
  • the pharmaceutical composition of the present invention is exemplified by a combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 20:1.
  • the pharmaceutical composition of the present invention is also exemplified by a combination of a tramadol material and the anticonvulsant drug gabapentin, wherein the tramadol material and gabapentin are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 2:1 to about 20:1.
  • the pharmaceutical composition of the present invention is further exemplified by a combination of a tramadol material and the anticonvulsant drug lamotrigine, wherein the tramadol material and lamotrigine are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:2 to about 1:8.
  • the pharmaceutical composition of the present invention is still further exemplified by a combination of a tramadol material and the anticonvulsant drug RWJ-333369, wherein the tramadol material and RWJ-333369 are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 20:1 or from about 1:1 to about 1:20.
  • the present invention also provides a pharmaceutical composition of the present invention for use in treating a condition of pain or a neurological or psychiatric disorder in a mammal in need thereof comprising administering to the mammal a therapeutically effective dose of a pharmaceutical composition for treating the condition of pain or the neurological or psychiatric disorder comprising a combination of a tramadol material and said anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 300:1 or from about 1:1 to about 1:300.
  • An embodiment of said use of the present invention comprises the administration of a therapeutically effective dose of a pharmaceutical composition comprising a combination of a tramadol material and said anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 100:1 or from about 1:1 to about 1:100.
  • Another embodiment of said use of the present invention comprises the administration of a therapeutically effective dose of a pharmaceutical composition comprising a combination of a tramadol material and said anticonvulsant drug, wherein the tramadol material and the anticonvulsant drug are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 30:1 or from about 1:1 to about 1:30.
  • the use of the present invention is exemplified by the administration of a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 20:1.
  • the use of the present invention is also exemplified by the administration of a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug gabapentin, wherein the tramadol material and gabapentin are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 2:1 to about 20:1.
  • the use of the present invention is further exemplified by the administration of a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug lamotrigine, wherein the tramadol material and lamotrigine are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:2 to about 1:8.
  • the use of the present invention is still further exemplified by the administration of a therapeutically effective dose of the pharmaceutical composition comprising a combination of a tramadol material and the anticonvulsant drug RWJ-333369, wherein the tramadol material and RWJ-333369 are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 20:1 or from about 1:1 to about 1:20.
  • the tramadol material is any one of (1 R ,2 R or 1 S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol (tramadol), its N-oxide derivative ("tramadol N-oxide"), and its O-desmethyl derivative ("O-desmethyl tramadol”) or mixtures thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts of the amines, such as the hydrochloride salt, solvates and polymorphs of the tramadol material. Tramadol is commercially available from Grunenthal or may be made by the process described in U. S. Patent No. 3,652,589.
  • Tramadol N-oxide is prepared by treating tramadol as a free base with an oxidizing agent, e.g., hydrogen peroxide (30%), in an organic solvent, e.g., methanol or isopropanol, with, but preferably without heating.
  • an oxidizing agent e.g., hydrogen peroxide (30%)
  • organic solvent e.g., methanol or isopropanol
  • PtO 2 or preferably Pt/C for about a day, to destroy the excess hydrogen peroxide.
  • the mixture is filtered, followed by the evaporation of the filtrate and then the residue is recrystallized from an organic solvent mixture, e.g., methylene chloride/ethyl acetate.
  • O-desmethyl tramadol is prepared by treating tramadol as a free base under O-demethylating reaction conditions, e.g., reacting it with a strong base such as NaOH or KOH, thiophenol and diethylene glycol (DEG) with heating to reflux (Wildes, et al., J. Org. Chem ., 1971 , 36, 721). The reaction takes about 1 h, followed by cooling and then quenching in water of the reaction mixture. The quenched mixture is acidified, extracted with an organic solvent such as ethyl ether, basified and then extracted with a halogenated organic solvent such as methylene chloride.
  • a strong base such as NaOH or KOH, thiophenol and diethylene glycol (DEG)
  • DEG diethylene glycol
  • the extract is then dried and the solvent evaporated to yield the O-desmethyl product, which may then be short-path distilled, converted to its corresponding salt, e.g., treated with an acidified (HCl/ethanol) solution, and recrystallized from an organic solvent mixture, e.g., ethanol/ethyl ether.
  • Anticonvulsant drugs are effective antiepileptic compounds some of which have been described as useful for the treatment of neuropathic pain and are topiramate, RWJ-333369, gabapentin or lamotrigine and are to be understood as including salts thereof, complexes thereof and mixtures of any of the foregoing.
  • the anticonvulsant drug topiramate is any one of the 2,3,4,5-bis-O-(1-methylethylidene)- ⁇ -D-fructopyranose sulfamates, its derivatives or mixtures thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including racemates thereof, e.g., the various ⁇ and ⁇ attachments, i.e., above and below the plane of the 6-membered ring structure, pharmaceutically acceptable salts, such as the hydrochloride salt, solvates and polymorphs of the topiramate material. Topiramate is commercially available from Ortho Pharmaceutical Corporation or may be made by the process described in U. S. Patent No. 4,513,006.
  • RWJ-333369 is disclosed in United States Patent 5,698,588 and described as useful in the treatment of central nervous system disorders, especially as anticonvulsants, antiepileptics, neuroprotective agents and centrally acting muscle relaxants.
  • RWJ-333369 is further described by the Chemical Abstracts Service (CAS) Index Name 1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)- and CAS Registry Number 194085-75-1.
  • CAS Chemical Abstracts Service
  • a tramadol material and said anticonvulsant drug are present in a ratio based on a fraction of their respective ED 50 values which ratio may vary from about 1:1 to about 300:1 or, reversibly, from about 1:1 to about 1:300; preferably, from about 1:1 to about 100:1 or from about 1:1 to about 1:100; and, more preferably, from about 1:1 to about 30:1 or from about 1:1 to about 1:30, depending upon the desired result.
  • An instant composition may comprise, for example, a combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 20:1; preferably, from about 1.5:1 to about 10:1; and, more preferably, from about 3:1 to about 5:1.
  • An instant composition may also comprise a combination of a tramadol material and the anticonvulsant drug gabapentin, wherein the tramadol material and gabapentin are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 2:1 to about 20:1; and, preferably, from about 9:1 to about 15:1.
  • An instant composition may further comprise a combination of a tramadol material and the anticonvulsant drug lamotrigine, wherein the tramadol material and lamotrigine are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:2 to about 1:8; and, preferably, about 1:3.
  • An instant composition may still further comprise a combination of a tramadol material and the anticonvulsant drug RWJ-333369, wherein the tramadol material and RWJ-333369 are present in a ratio based on a fraction of their respective ED 50 values, which ratio is from about 1:1 to about 20:1 or from about 1:1 to about 1:20; preferably, from about 1:1 to about 10:1 or from about 1:1 to about 1:10; and, more preferably, from about 1:1 to about 4:1 or from about 1:1 to about 1:4.
  • Compositions comprising a combination of a tramadol material and an anticonvulsant drug within these ratios exhibit synergistic effects.
  • a pharmaceutical composition according to the present invention comprises a therapeutically effective dose of a tramadol material for treating a condition of pain or a neurological or psychiatric disorder in a mammal in need thereof in combination with an anticonvulsant drug.
  • the instant composition comprises a combination of tramadol hydrochloride and an anticonvulsant drug selected from topiramate, gabapentin, lamotrigine or RWJ-333369.
  • compositions comprising a combination of a tramadol material and the anticonvulsant drug as the active ingredients in an intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral.
  • the composition may also be administered by means of an aerosol.
  • any of the usual pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
  • oral solid preparations such as, for example, powders, capsules and tablets
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be sugar-coated or enteric-coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • compositions of the present invention will generally be in the form of a dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, wherein the preferred amount of each of the active ingredient to be contained therein is determined by the aforementioned ratios.
  • the dosage unit is calculated based on the amount of active ingredient which may be given to a 70 kg human subject in a single dose.
  • An instant pharmaceutical composition may be given at a daily dose of from about 5 mg/day to about 8000 mg/day.
  • the precise therapeutically effective dose of the active ingredients will vary depending upon the relative amount of each active component being used, upon the particular tramadol material and anticonvulsant drug being used and upon the aforementioned synergistic ratios.
  • a single dose of a formulation of a pharmaceutical composition demonstrating synergistic activity may contain a therapeutically effective dose of active ingredient of from about 20 mg to about 400 mg of a combination of a tramadol material and the anticonvulsant drug; preferably, from about 20 mg to about 200 mg; more preferably, from about 20 mg to about 100 mg; and, most preferably, from about 20 mg to about 50 mg.
  • a 20 mg formulation of a pharmaceutical composition comprising a synergistic combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED 50 values, which ratio is about 3:1 will contain about 15 mg of a tramadol material and about 5 mg of topiramate.
  • the tramadol material and the anticonvulsant drug need not be present in the same formulation to achieve the results described herein. They may be administered individually at about the same time or in a single tablet.
  • a pharmaceutical composition of the present invention may be administered in a single daily dose or the total daily dose may be administered in divided doses of two, three or four times daily.
  • Optimal therapeutically effective doses to be administered may be readily determined by those skilled in the art, will vary with the particular combination of a tramadol material and the anticonvulsant drug used, the amount of active ingredients used in a synergistic ratio based on a fraction of their respective ED 50 values, the strength of the preparation, the mode of administration and the advancement of the condition or disorder treated.
  • factors associated with the particular subject being treated including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutically effective level.
  • compositions of the present invention are useful for treating conditions of pain and certain neurological and psychiatric disorders in mammals by the administration of a composition comprising a combination of a tramadol material and the anticonvulsant drug.
  • a composition comprising a combination of a tramadol material and the anticonvulsant drug.
  • Those skilled in the art of treating mammalian pain know that the types of pain experienced by mammals are varied.
  • conditions of mammalian pain include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain and neuropathic pain states, all of which would include acute pain such as caused by acute injury, trauma or surgery; chronic pain such as caused by neuropathic conditions, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain syndromes or cluster or migraine headaches; and inflammatory condition pain such as caused by osteoarthritis, rheumatoid arthritis or as sequela to disease, acute injury or trauma.
  • composition of the present invention is also useful in the treatment of certain neurological and psychiatric disorders including, but not limited to, bipolar disorder, psychosis, post-traumatic stress disorder, social phobia, obsessive-compulsive disorder; movement disorders such as akathisia, restless leg syndrome, tardive dyskinesia or central tremor; neurodegeneration in diseases such as ischemias (acute, delayed, recovery) or degeneration of nervous system cells due to Alzheimer's disease, Parkinson's disease or surgery; particularly, open-chest surgery; and, more particularly, open-heart or bypass surgery.
  • certain neurological and psychiatric disorders including, but not limited to, bipolar disorder, psychosis, post-traumatic stress disorder, social phobia, obsessive-compulsive disorder; movement disorders such as akathisia, restless leg syndrome, tardive dyskinesia or central tremor; neurodegeneration in diseases such as ischemias (acute, delayed, recovery) or degeneration of nervous system cells due to Alzheimer's
  • composition comprising a combination of a tramadol material and an anticonvulsant drug in greater particularity and are intended to be a way of illustrating but not limiting the invention.
  • the procedure used to detect and compare the synergistic effect of the composition of the present invention for which there is a good correlation with human efficacy for the treatment of pain is the procedure for the measurement of allodynia found in the Chung Model (Chaplan S.R., Bach F.W., Pogrel J.W., Chung J.M. and Yaksh T.L., Quantitative Assessment of Tactile Allodynia in the Rat Paw, J . Neurosci. Meth., 1994 , 53, 55-63 and Kim S.H. and Chung J.M., An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat, Pain, 1992 , 50, 355-363).
  • the antiallodynic effect of the composition of the present invention in the Chung Model is expressed in % MPE (Maximum Possible Effect).
  • the rats were anesthetized with isoflurane inhalant anesthesia.
  • the left lumbar spinal nerve at the level of L5 was tightly ligated (4-0 silk suture) distal to the dorsal root ganglion and prior to entrance into the sciatic nerve, as described by Kim and Chung.
  • the incisions were closed and the rats were allowed to recover under conditions described above. This procedure results in mechanical allodynia in the left hind paw.
  • the sham operation when performed, consisted of a similar surgical procedure lacking only the final ligation of the spinal nerve.
  • the dosing materials were all prepared in the vehicle, a suspension of 0.5% hydroxypropyl methylcellulose in distilled water; drug weights were calculated as the free base.
  • the tramadol solution was prepared first, and the appropriate volume of this solution was added to a neat amount of the anticonvulsant to give the final dosing suspension.
  • Drug weights were calculated as the free base, and the ratios used were based on the respective ED 50 values of tramadol and the anticonvulsant. The necessary doses for each ratio were prepared separately and dosed orally in a volume of 10 mL/kg per rat.
  • the Chung Model rats were all dosed orally with the composition comprising a combination of tramadol hydrochloride (calculated as the base) and the anticonvulsant drug (calculated as the base) or the composition of each agent separately dissolved in distilled water or dissolved in a suspension of 0.5% hydroxypropyl methylcellulose in distilled water.
  • the dosing volume was 10 mL/kg.
  • the rats were intubated with various doses of tramadol hydrochloride alone, anticonvulsant drug alone, combined doses of tramadol hydrochloride and anticonvulsant or vehicle such as distilled water or a suspension of 0.5% hydroxypropyl methylcellulose in distilled water.
  • ED 50mix was determined from the dose-response curve for a specific fixed-ratio of the components; ED 50add was calculated from the ED 50 values for the individual drugs. Z mix was then compared to Z add via a Student's t-test.
  • tramadol hydrochloride was determined at precise ratios of tramadol hydrochloride and the anticonvulsant drug. Multiple (typically 4-6) coded doses of each selected combination were studied for synergistic antiallodynic effect using an experimental design which permitted the complete randomization of the separate dosage forms tested.
  • the fraction of the ED 50 values for the individual drugs alone lie on their respective axes.
  • the ED 50 value of tramadol alone at 2 hours post-dosing was 94.47 mg/kg and is illustrated in Figure 1 at the value of 1.
  • the ED 50 value of topiramate alone at 2 hours post-dosing was 98.04 mg/kg and is illustrated in Figure 1 at the value of 1. Therefore, the line joining the ED 50 value of the two separate drugs represents the calculated simple additivity of the antiallodynic effect at different ratios.
  • the point at the asterisked letter (e.g., A*) represents the theoretical additive ED 50 value (Z add ) for a particular dose ratio.
  • the points labeled A, B and C represent the actual, experimentally determined fraction of the ED 50 values (Z mix ) for the tramadol hydrochloride and topiramate combinations in the ratios of 3:1, 1:1 and 1:3, respectively.
  • the fraction of the ED 50 values for the individual drugs alone lie on their respective axes.
  • the ED 50 value of tramadol alone at 1 hour post-dosing was 48.56 mg/kg and is illustrated in Figure 2 at the value of 1.
  • the ED 50 value of RWJ-333369 alone at 1 hours post-dosing was 77.37 mg/kg and is illustrated in Figure 2 at the value of 1. Therefore, the line joining the ED 50 value of the two separate drugs represents the calculated simple additivity of the antiallodynic effect at different ratios.
  • the point at the asterisked letter (e.g., A*) represents the theoretical additive ED 50 value (Z add ) for a particular dose ratio.
  • the points labeled A, B and C represent the actual, experimentally determined fraction of the ED 50 values (Z mix ) for the tramadol hydrochloride and RWJ-333369 combinations in the ratios (of the ED 50 values) of 4:1, 1:1 and 1:4, respectively.
  • the procedure used to detect and compare the synergistic effect of the composition of the present invention for which there is a good correlation with human efficacy for the treatment of pain is the procedure, with minor modifications, for the measurement of antinociception found in the Mouse Hot Plate Model (Eddy and Leimbach, J . Pharmacol. Exp. Ther., 1953 , 107, 385-393; and O'Callaghan and Holtzman, J . Pharmacol. Exp. Ther., 1975 , 192, 497-505). Mice were placed on a heated surface (48 °C) and the time interval (seconds) between placement and a shaking, licking, or tucking of the hind paw was recorded as the predrug latency response. This same procedure was repeated at various times after the test drug was administered p.o., 10 mL/kg.
  • % MPE % maximal possible effect
  • the dosing materials were all prepared in the vehicle, a suspension of 0.5% hydroxypropyl methylcellulose in distilled water; and drug weights were calculated as the free base.
  • the tramadol solution was prepared first, and the appropriate volume of this solution was added to a neat amount of topiramate to give the final dosing suspension.
  • Drug weights were calculated as the free base.
  • the necessary doses were prepared separately and dosed orally in a volume of 10 mL/kg per mouse.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Rheumatology (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP00957321A 1999-08-20 2000-08-09 Composition comprising a tramadol material and an anticonvulsant drug Expired - Lifetime EP1210118B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK00957321T DK1210118T3 (da) 2000-08-09 2000-08-09 Sammensætning omfattende et tramadolmateriale og et antikonvulsionslægemiddel

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US15020199P 1999-08-20 1999-08-20
US150201P 1999-08-20
PCT/US2000/021622 WO2001013904A2 (en) 1999-08-20 2000-08-09 Composition comprising a tramadol material and an anticonvulsant drug

Publications (2)

Publication Number Publication Date
EP1210118A2 EP1210118A2 (en) 2002-06-05
EP1210118B1 true EP1210118B1 (en) 2004-12-08

Family

ID=22533492

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00957321A Expired - Lifetime EP1210118B1 (en) 1999-08-20 2000-08-09 Composition comprising a tramadol material and an anticonvulsant drug

Country Status (31)

Country Link
US (1) US6562865B1 (zh)
EP (1) EP1210118B1 (zh)
JP (1) JP4977297B2 (zh)
KR (1) KR100758609B1 (zh)
CN (1) CN1198651C (zh)
AR (1) AR032132A1 (zh)
AT (1) ATE284223T1 (zh)
AU (1) AU782759B2 (zh)
BG (1) BG65996B1 (zh)
BR (1) BRPI0013439B8 (zh)
CA (1) CA2381797C (zh)
CO (1) CO5190667A1 (zh)
CR (1) CR6593A (zh)
CZ (1) CZ2002524A3 (zh)
DE (1) DE60016602T2 (zh)
EA (1) EA006598B1 (zh)
ES (1) ES2234651T3 (zh)
HU (1) HUP0203198A3 (zh)
IL (2) IL148019A0 (zh)
MX (1) MXPA02001820A (zh)
MY (1) MY136985A (zh)
NO (1) NO332342B1 (zh)
NZ (1) NZ517106A (zh)
PL (1) PL213323B1 (zh)
PT (1) PT1210118E (zh)
SK (1) SK286621B6 (zh)
TR (1) TR200201067T2 (zh)
TW (1) TWI259769B (zh)
UA (1) UA75868C2 (zh)
WO (1) WO2001013904A2 (zh)
ZA (1) ZA200201403B (zh)

Families Citing this family (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU219332B (hu) 1991-09-06 2001-03-28 Mcneilab Inc Transz-(+)-2-[(dimetil-amino)-metil]-1-(3-metoxi-fenil)-ciklohexanolt és acetaminofent tartalmazó szinergetikus gyógyszerkészítmények
US7164034B2 (en) 1999-06-10 2007-01-16 Pfizer Inc. Alpha2delta ligands for fibromyalgia and other disorders
PT1210118E (pt) 1999-08-20 2005-02-28 Ortho Mcneil Pharm Inc Composicao compreendendo um material tramadol e um farmaco anticonvulsivo
DE19940740A1 (de) * 1999-08-31 2001-03-01 Gruenenthal Gmbh Pharmazeutische Salze
DE10049483A1 (de) * 2000-09-29 2002-05-02 Gruenenthal Gmbh Substituierte 1-Aminobutan-3-ol-Derivate
MXPA04002709A (es) * 2001-09-24 2005-06-06 Johnson & Johnson Derivados articonvulsivos utiles para el tratamiento del sindrome de extremidades inquietas y trastorno periodico del movimiento de extremidades.
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
IL163720A0 (en) * 2002-02-26 2005-12-18 Ortho Mcneil Pharm Inc Co-therapy for the treatment of migraine comprising anticonvulsant derivatives and anti-migraine agents
CA2477923C (en) 2002-03-01 2021-02-23 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
EP1364649A1 (en) 2002-05-23 2003-11-26 Cilag AG Adduct of topiramate and tramadol hydrochioride and uses thereof
CA2489984A1 (en) 2002-06-21 2003-12-31 Transform Pharmaceuticals, Inc. Pharmaceutical compositions with improved dissolution
ES2421516T3 (es) 2002-11-06 2013-09-03 Dana Farber Cancer Inst Inc Composiciones para tratar el cáncer usando el inhibidor de proteasomas PS-341
CA2506807A1 (en) * 2002-12-13 2004-07-01 Cilag Ag Controlled release preparations comprising tramadol and topiramate
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
KR101043789B1 (ko) * 2003-03-31 2011-06-27 (주)에이스딕시오 디지털 신호 처리를 이용한 전력 측정기 및 그 전력 측정 방법과 그 방법을 수행하는 프로그램을 기록한 컴퓨터로 읽을 수 있는 기록매체
JP2007538250A (ja) * 2004-05-19 2007-12-27 ファイザー・インク アッセイ法
AR049646A1 (es) * 2004-06-16 2006-08-23 Janssen Pharmaceutica Nv Derivados de sulfamato y sulfamida utiles para el tratamiento de la epilepsia y trastornos relacionados
MY147767A (en) * 2004-06-16 2013-01-31 Janssen Pharmaceutica Nv Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders
ES2310366T3 (es) * 2004-08-24 2009-01-01 Janssen Pharmaceutica Nv Nuevos derivados de heteroaril sulfonamida benzo-condensada utiles como agentes anticonvulsivos.
AU2005295787A1 (en) * 2004-10-15 2006-04-27 Janssen Pharmaceutica, N.V. Carbamate compounds for use in treating neurodegenerative disorders
CN101232868A (zh) * 2005-04-19 2008-07-30 阿尔扎公司 曲马多和加巴喷丁的控释递药剂型
AU2006249577A1 (en) 2005-05-20 2006-11-30 Janssen Pharmaceutica N.V. Process for preparation of sulfamide derivatives
US20070021500A1 (en) * 2005-07-12 2007-01-25 Twyman Roy E Methods for neuroprotection
WO2007053596A1 (en) * 2005-10-31 2007-05-10 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
MXPA05011735A (es) * 2005-11-01 2007-04-30 Leopoldo Espinosa Abdala Composiciones farmaceuticas que comprenden combinaciones de analgesicos y anticonvulsivantes para el tratamiento del dolor agudo y cronico.
AR058389A1 (es) * 2005-12-19 2008-01-30 Janssen Pharmaceutica Nv Uso de derivados heterociclicos benzo-fusionados de sulfamida para el tratamiento de la obesidad
US8716231B2 (en) 2005-12-19 2014-05-06 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain
US8937096B2 (en) * 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
US8497298B2 (en) * 2005-12-19 2013-07-30 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels
US8691867B2 (en) * 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US20070155827A1 (en) * 2005-12-19 2007-07-05 Smith-Swintosky Virginia L Use of benzo-fused heterocycle sulfamide derivatives for the treatment of depression
US20070155823A1 (en) * 2005-12-19 2007-07-05 Smith-Swintosky Virginia L Use of benzo-fused heterocycle sulfamide derivatives as neuroprotective agents
US20070191461A1 (en) * 2006-02-15 2007-08-16 Smith-Swintosky Virginia L Use of benzo-heteroaryl sulfamide derivatives for the treatment of migraine
US20070191449A1 (en) * 2006-02-15 2007-08-16 Smith-Swintosky Virginia L Use of Benzo-Heteroaryl Sulfamide Derivatives for the Treatment of Depression
US20070191474A1 (en) * 2006-02-15 2007-08-16 Smith-Swintosky Virginia L Use of benzo-fused heterocyle sulfamide derivatives for the treatment of migraine
US20070191452A1 (en) * 2006-02-15 2007-08-16 Smith-Swintosky Virginia L Use of benzo-heteroaryl sulfamide derivatives for the treatment of pain
TW200812574A (en) * 2006-05-19 2008-03-16 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders
AU2007253814A1 (en) 2006-05-19 2007-11-29 Janssen Pharmaceutica N.V. Co-therapy for the treatment of epilepsy
EP2037965B1 (en) * 2006-06-15 2017-08-30 UCB Pharma GmbH Pharmaceutical composition with synergistic anticonvulsant effect
WO2008027557A2 (en) * 2006-08-31 2008-03-06 Spherics, Inc. Topiramate compositions and methods of enhancing its bioavailability
EP2089015B1 (en) * 2006-10-27 2010-11-24 Janssen Pharmaceutica, N.V. Methods for treating disruptive behavior disorders
EP1973528B1 (en) 2006-11-17 2012-11-07 Supernus Pharmaceuticals, Inc. Sustained-release formulations of topiramate
WO2008070670A2 (en) * 2006-12-04 2008-06-12 Supernus Pharmaceuticals, Inc. Enhanced immediate release formulations of topiramate
US20090076128A1 (en) * 2007-09-15 2009-03-19 Protia Llc Deuterium-enriched topiramate
US8263652B2 (en) * 2007-10-31 2012-09-11 Sk Biopharmaceuticals Co., Ltd. Stabilized pediatric suspension of carisbamate
US8356315B2 (en) * 2007-12-03 2013-01-15 Koncelik Jr Lawrence J Setting television default channel
ES2601852T3 (es) 2008-01-25 2017-02-16 Xenoport, Inc. Forma cristalina de sales de calcio de ácidos (3S)-aminometil-5-metil-hexanoicos y métodos de uso
WO2009094563A2 (en) 2008-01-25 2009-07-30 Xenoport, Inc. Crystalline form of calcium-salts of (3s)-aminomethyl-b-methyl-hexanoic acids and methods of use
WO2009094577A2 (en) 2008-01-25 2009-07-30 Xenoport, Inc. Mesophasic forms of (3s)-aminomethyl-5-methyl-hexanoic acid prodrugs and methods of use
US20090247616A1 (en) * 2008-03-26 2009-10-01 Smith-Swintosky Virginia L Use of benzo-fused heterocyle sulfamide derivatives for the treatment of anxiety
US20090247617A1 (en) * 2008-03-26 2009-10-01 Abdel-Magid Ahmed F Process for the preparation of benzo-fused heteroaryl sulfamates
SG176464A1 (en) 2008-05-09 2011-12-29 Agency Science Tech & Res Diagnosis and treatment of kawasaki disease
NZ590682A (en) 2008-06-23 2012-09-28 Janssen Pharmaceutica Nv Crystalline form of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide
US20100003322A1 (en) * 2008-07-03 2010-01-07 Lai Felix S Enteric coated hydrophobic matrix formulation
US8815939B2 (en) * 2008-07-22 2014-08-26 Janssen Pharmaceutica Nv Substituted sulfamide derivatives
PE20142372A1 (es) * 2008-09-05 2015-02-04 Gruenenthal Chemie Combinacion farmaceutica de 3-(3-dimetilamino-1-etil-2-metil-propil)-fenol y un antiepileptico
US20100190752A1 (en) 2008-09-05 2010-07-29 Gruenenthal Gmbh Pharmaceutical Combination
WO2011023392A1 (en) 2009-08-28 2011-03-03 Grünenthal GmbH Pharmaceutical combination comprising 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol or 6-dimethylaminomethyl-1-(3-hydroxy-phenyl)-cyclohexane-1,3-diol and an antiepileptic
EP2383255A1 (en) 2010-04-28 2011-11-02 Lacer, S.A. New compounds, synthesis and use thereof in the treatment of pain
KR101786818B1 (ko) 2010-07-30 2017-10-18 도레이 카부시키가이샤 신경장애성 동통의 치료제 또는 예방제
EP2530072A1 (en) 2011-06-03 2012-12-05 Lacer, S.A. New compounds, synthesis and use thereof in the treatment of pain
US10702485B2 (en) 2011-07-09 2020-07-07 Syntrix Biosystems Inc. Compositions and methods for overcoming resistance to tramadol
RU2533979C1 (ru) * 2013-03-11 2014-11-27 государственное бюджетное образовательное учреждение высшего профессионального образования "Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова" Министерства здравоохранения Российской Федерации Способ лечения центральных стенозирующих злокачественных опухолей трахеи и бронхов
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
DE102013009114A1 (de) * 2013-05-29 2014-12-04 Franz Gerstheimer Pharmazeutische Zusammensetzung zur Überwindung von Metabolisierungsproblemen
WO2017118726A1 (en) 2016-01-06 2017-07-13 Lonza Ltd Inhibition of protein degradation for improved production
US11464756B1 (en) 2017-05-19 2022-10-11 Jerry Darm Mecuna pruriens, L-DOPA and 5-HTP based dietary supplements, pharmaceutical formulations and uses thereof
WO2019183146A1 (en) 2018-03-20 2019-09-26 Abraxis Bioscience, Llc Methods of treating central nervous system disorders via administration of nanoparticles of an mtor inhibitor and an albumin
WO2020044070A1 (es) 2018-08-30 2020-03-05 Grünenthal GmbH Combinación farmacéutica sinérgica que comprende tramadol clorhidrato y pregabalina, y su uso para el tratamiento del dolor neuropático
WO2020262317A1 (ja) * 2019-06-27 2020-12-30 Ｎｕｍａｎ Ｌａｂｏ合同会社 認知症の治療及び予防薬
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3652589A (en) 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US3562589A (en) * 1968-09-09 1971-02-09 Ite Imperial Corp Electrically resetting undervoltage trip for circuit breakers
US4513006A (en) * 1983-09-26 1985-04-23 Mcneil Lab., Inc. Anticonvulsant sulfamate derivatives
US4587252A (en) * 1984-12-18 1986-05-06 Brighton Pharmaceutical, Inc. Hydrocodone/ibuprofen pharmaceutical compositions and method
US4569937A (en) * 1985-02-11 1986-02-11 E. I. Du Pont De Nemours And Company Analgesic mixture of oxycodone and ibuprofen
ZW14392A1 (en) 1991-09-06 1994-05-11 Mcneilab Inc "Compositions comprising a tramadol material and any of codeine, oxycodone or bydrocodone and their use"
HU219332B (hu) * 1991-09-06 2001-03-28 Mcneilab Inc Transz-(+)-2-[(dimetil-amino)-metil]-1-(3-metoxi-fenil)-ciklohexanolt és acetaminofent tartalmazó szinergetikus gyógyszerkészítmények
US5516803A (en) 1991-10-30 1996-05-14 Mcneilab, Inc. Composition comprising a tramadol material and a non-steroidal anti-inflammatory drug
GB9417532D0 (en) * 1994-08-31 1994-10-19 Zeneca Ltd Aromatic compounds
DK0920422T3 (da) * 1996-08-14 2003-03-17 Searle & Co Krystallinsk form af 4-[5-methyl-3-phenylisoxazol-4-yl]benzensulfonamid
WO1998007447A1 (en) * 1996-08-23 1998-02-26 Algos Pharmaceutical Corporation Anticonvulsant containing composition for treating neuropathic pain
US5760007A (en) * 1997-07-16 1998-06-02 Ortho Pharmaceutical Corporation Anticonvulsant derivatives useful in treating neuropathic pain
ATE279919T1 (de) * 1997-08-15 2004-11-15 Carolyn Ann Fairbanks Agmatin für die behandlung neuropathischer schmerzen
ES2253825T3 (es) * 1997-09-08 2006-06-01 Warner-Lambert Company Llc Composiciones analgesicas que comprenden compuestos antiepilepticos y procedimientos para usar las mismas.
PT1210118E (pt) 1999-08-20 2005-02-28 Ortho Mcneil Pharm Inc Composicao compreendendo um material tramadol e um farmaco anticonvulsivo

Also Published As

Publication number Publication date
NO332342B1 (no) 2012-09-03
HUP0203198A2 (hu) 2003-02-28
EA200200183A1 (ru) 2002-08-29
WO2001013904A3 (en) 2001-06-14
KR20020025221A (ko) 2002-04-03
ZA200201403B (en) 2003-07-30
EP1210118A2 (en) 2002-06-05
CR6593A (es) 2009-01-16
TWI259769B (en) 2006-08-11
BRPI0013439B1 (pt) 2012-07-24
NO20020728L (no) 2002-04-05
WO2001013904A2 (en) 2001-03-01
IL148019A (en) 2012-03-29
BRPI0013439B8 (pt) 2021-07-06
MY136985A (en) 2008-12-31
DE60016602T2 (de) 2005-11-03
DE60016602D1 (de) 2005-01-13
NO20020728D0 (no) 2002-02-13
ES2234651T3 (es) 2005-07-01
CO5190667A1 (es) 2002-08-29
BG65996B1 (bg) 2010-09-30
HUP0203198A3 (en) 2005-07-28
TR200201067T2 (tr) 2002-09-23
BG106420A (bg) 2002-09-30
SK286621B6 (sk) 2009-02-05
AR032132A1 (es) 2003-10-29
CZ2002524A3 (cs) 2002-11-13
JP2003507421A (ja) 2003-02-25
PL353266A1 (en) 2003-11-03
MXPA02001820A (es) 2003-07-14
SK2262002A3 (en) 2003-02-04
US6562865B1 (en) 2003-05-13
CN1198651C (zh) 2005-04-27
UA75868C2 (en) 2006-06-15
CN1379686A (zh) 2002-11-13
CA2381797A1 (en) 2001-03-01
AU782759B2 (en) 2005-08-25
PL213323B1 (pl) 2013-02-28
CA2381797C (en) 2008-04-15
ATE284223T1 (de) 2004-12-15
AU6895800A (en) 2001-03-19
KR100758609B1 (ko) 2007-09-13
EA006598B1 (ru) 2006-02-24
BRPI0013439A (pt) 2002-04-30
IL148019A0 (en) 2002-09-12
PT1210118E (pt) 2005-02-28
NZ517106A (en) 2005-04-29
JP4977297B2 (ja) 2012-07-18

Similar Documents

Publication Publication Date Title
EP1210118B1 (en) Composition comprising a tramadol material and an anticonvulsant drug
EP0566709B1 (en) Composition comprising a tramadol compound and acetaminophen, and its use
KR100236666B1 (ko) 트라마돌 및 코데인, 옥시코돈 또는 하이드로코돈을 함유하는 조성물 및 그의 용도
US4599342A (en) Pharmaceutical products providing enhanced analgesia
CA1241604A (en) Pharmaceutical products providing enhanced analgesia
US8710040B2 (en) Pharmaceutical composition comprising gabapentin or an analogue thereof and an α-aminoamide and its analgesic use
AU3384200A (en) Composition comprising a tramadol material and a selective cox-2 inhibitor drug
AU2002333374A1 (en) Pharmaceutical composition comprising gabapentin or an analogue thereof and an (alpha)- aminoamide and its analgesic use
MXPA05011735A (es) Composiciones farmaceuticas que comprenden combinaciones de analgesicos y anticonvulsivantes para el tratamiento del dolor agudo y cronico.
EP0346445A1 (en) Dextrorphan potentiator for anticonvulsant composition and method
KR20130103342A (ko) 신경장애성 동통의 치료제 또는 예방제

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020318

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20020820

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60016602

Country of ref document: DE

Date of ref document: 20050113

Kind code of ref document: P

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20050112

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20050400276

Country of ref document: GR

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2234651

Country of ref document: ES

Kind code of ref document: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

ET Fr: translation filed
26N No opposition filed

Effective date: 20050909

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: ORTHO-MCNEIL PHARMACEUTICAL, INC.

Free format text: ORTHO-MCNEIL PHARMACEUTICAL, INC.#U.S. ROUTE NO.202, P.O. BOX 300#RARITAN, NJ 08869-0602 (US) -TRANSFER TO- ORTHO-MCNEIL PHARMACEUTICAL, INC.#U.S. ROUTE NO.202, P.O. BOX 300#RARITAN, NJ 08869-0602 (US)

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 17

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 18

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20190724

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20190814

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20190813

Year of fee payment: 20

Ref country code: MC

Payment date: 20190726

Year of fee payment: 20

Ref country code: ES

Payment date: 20190902

Year of fee payment: 20

Ref country code: PT

Payment date: 20190807

Year of fee payment: 20

Ref country code: FI

Payment date: 20190812

Year of fee payment: 20

Ref country code: SE

Payment date: 20190813

Year of fee payment: 20

Ref country code: IT

Payment date: 20190821

Year of fee payment: 20

Ref country code: FR

Payment date: 20190711

Year of fee payment: 20

Ref country code: CY

Payment date: 20190805

Year of fee payment: 20

Ref country code: IE

Payment date: 20190813

Year of fee payment: 20

Ref country code: DE

Payment date: 20190730

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20190710

Year of fee payment: 20

Ref country code: BE

Payment date: 20190716

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20190808

Year of fee payment: 20

Ref country code: AT

Payment date: 20190725

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20190819

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60016602

Country of ref document: DE

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

Expiry date: 20200809

REG Reference to a national code

Ref country code: NL

Ref legal event code: MK

Effective date: 20200808

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20200808

REG Reference to a national code

Ref country code: BE

Ref legal event code: MK

Effective date: 20200809

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 284223

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200809

REG Reference to a national code

Ref country code: FI

Ref legal event code: MAE

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20200819

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20200808

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20200809

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20201126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20200810